The present invention relates generally to the area of drug delivery, and more particularly to the area of dermal and transdermal drug delivery of interferon-xcex1.
Interferons (IFNs) are a well known family of cytokines secreted by a large variety of eukaryotic cells upon exposure to various mitogens. The interferons have been classified by their chemical and biological characteristics into three groups: IFN-xcex1 (leukocytes), IFN-beta (fibroblasts), and IFN-gamma (lymphocytes). IFN-alpha and beta are known as Type I interferons; IFN-gamma is known as Type II or immune interferon. The IFNs exhibit anti-viral, immunoregulatory, and antiproliferative activity.
Interferons are produced and secreted by most nucleated cells in response to viral infection as well as other antigenic stimuli. Interferons render cells resistant to viral infection and exhibit a wide variety of actions on cells. They exert their cellular activities by binding to specific membrane receptors on the cell surface. Once bound to the cell membrane, interferons initiate a complex sequence of intracellular events, including the induction of certain enzymes, suppression of cell proliferation, immunomodulating activities such as enhancement of the phagocytic activity of macrophages and augmentation of the specific cytotoxicity of lymphocytes for target cells, and inhibition of virus replication in virus-infected cells.
Oral, nasal, transdermal and even buccal and rectal routes are being investigated as potentially feasible routes to administer protein drugs, such as interferons. However, administration of polypeptides poses particular concerns. For example, the site, or route, of administration is frequently hostile to the polypeptide, e.g., orally delivered proteins are subjected to harsh conditions prior to absorption through the gastro-intestinal tract. Similarly, during absorption through the nasal mucosa considerable metabolism may occur. Another problem is that poor absorption of sufficient amounts of drug through respective barrier layers at the site of administration may be a significant factor in failure to achieve a pharmacological response.
Of these alternative routes of administration, transdermal drug delivery offers several advantages over that more traditional delivery methods, such as injections and oral delivery. Compared to oral delivery, transdermal delivery avoids gastrointestinal drug metabolism, reduces the first pass effect, and can provide a sustained release of the drug. Compared to injections, transdermal delivery eliminates the associated pain and the possibility of infection.
Theoretically, the transdermal route of drug administration could be advantageous in the delivery of many therapeutic polypeptides and proteins because these compounds are susceptible to gastrointestinal degradation and exhibit poor gastrointestinal uptake. Some proteins are cleared rapidly from the blood and need to be delivered at a sustained rate in order to maintain their blood concentration at a therapeutic level.
While transdermal delivery offers an advantageous alternative to oral delivery and injections, its applications are restricted to only a few drugs because of the extremely low skin permeability to drugs. A variety of approaches have been disclosed for enhancing transdermal uptake of drugs. These include the use of chemicals to either modify the structure of the skin or to increase the drug concentration in a transdermal device, application of electric fields to create transient transport pathways (electroporation) or to increase the mobility of charged drugs through the skin (inotophoresis), and application of ultrasound (sonophoresis).
Accordingly, it is an object of the invention to provide a composition for administration of an interferon polypeptide, transdermally.
It is a specific object of the invention to provide a composition for transdermal administration of interferon-xcex1 that delivers a sufficient amount of the drug for treatment of a condition that response to interferon-xcex1.
In one aspect, the invention includes an interferon-xcex1 composition comprising biphasic lipid vesicles comprised of (i) a lipid bilayer comprising a phospholipid and a fatty acylated amino acid; (ii) an oil-in-water emulsion entrapped in the biphasic lipid vesicles, where the oil-in-water emulsion is stabilized by a surfactant; and (iii) interferon-xcex1 entrapped in the vesicles. The composition when applied to the skin of a subject is effective to administer a therapeutically effective amount of interferon-xcex1.
In one embodiment, the acylated amino acid is represented by the formula: 
wherein R1 is an acyl group having from 1-20 carbons, R2 is hydrogen or an alkyl group, and R3 corresponds to a modified or unmodified R group of a selected amino acid.
The acylated amino acid, in one embodiment, is selected to achieve dermal administration of interferon-xcex1 for treatment of a local, topical condition.
In another embodiment, the acylated amino acid is effective to achieve transdermal administration of interferon-xcex1.
In a preferred embodiment, R2 in the acylated amino acid is ((CO)C19H39). In particular, when R2 is ((CO)C19H39) the amino acid is serine or threonine. Another preferred acylated amino acid is monolauroyl lysine.
In still another embodiment, the oil-in-water emulsion in the biphasic lipid vesicles further comprises a fatty alcohol. For example, the fatty alcohol can have between about 8-24 carbon atoms. In another embodiment, the oil-in-water emulsion further comprises a triglyceride, such as pharmaceutically-acceptable oil, such as canola oil and olive oil.
In yet another embodiment, the oil-in-water emulsion is further comprised of a fatty glyceride dispersed in the water phase and stabilized by the surfactant. Such a fatty glyceride can be, for example, glycerol monostearate.
The lipid bilayer of the vesicles can further comprise of a sterol.
In another aspect, the invention includes a composition for administration of interferon-xcex1, comprising biphasic lipid vesicles comprised of (i) a lipid bilayer comprised of a phospholipid and an amino acid acylated; (ii) an oil-in-water emulsion entrapped in the biphasic lipid vesicles, where the oil-in-water emulsion is comprised of a triglyceride that is dispersed in a water phase containing a fatty alcohol and that is stabilized by a surfactant; and (iii) interferon-xcex1 entrapped in the vesicles. The composition when applied to the skin of a subject is effective to administer a therapeutically effective amount of interferon-xcex1.
In still another aspect, the invention includes a method of administering a therapeutically effective amount of interferon-xcex1 to a subject, comprising preparing biphasic lipid vesicles as described above. The biphasic lipid vesicles are then contacted with the skin of a subject for transdermal or dermal delivery, depending on the selected acylated amino acid.
In a further aspect, the invention includes a method of treating human papilloma virus in a subject. The method includes preparing biphasic lipid vesicles as described above and contacting the biphasic lipid vesicles with the skin of a subject, or more preferably, applying the lipid vesicles to the site of the infection.
These and other objects and features of the invention will be more fully appreciated when the following detailed description of the invention is read in conjunction with the accompanying drawings.